A form of the metabolic syndrome associated with mutations in DYRK1B.
A form of the metabolic syndrome associated with mutations in DYRK1B.
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DOI：
10.1056/nejmoa1301824
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发表时间：
2014-05-15
期刊：
影响因子：
--
通讯作者：
Mani A
中科院分区：
文献类型：
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作者：
Keramati AR;Fathzadeh M;Go GW;Singh R;Choi M;Faramarzi S;Mane S;Kasaei M;Sarajzadeh-Fard K;Hwa J;Kidd KK;Babaee Bigi MA;Malekzadeh R;Hosseinian A;Babaei M;Lifton RP;Mani A
遗传分析已经成功地确定了个别心血管危险因素的致病突变。在绘制心血管风险特征群（如代谢综合征）易感基因图谱方面，成功率较为有限。我们确定了三个共同遗传早发性冠状动脉疾病、向心性肥胖、高血压和糖尿病的大家族。我们使用连锁分析和全外显子组测序来确定致病基因。在DYRK 1B中发现了一个创始者突变，在高度保守的激酶样结构域的102位用半胱氨酸取代精氨酸。在所有受影响的家族成员中，突变与临床综合征精确共分离，而在未受影响的家族成员和无关对照中不存在。疾病基因的功能表征显示，DYRK 1B编码的非突变蛋白抑制SHH（音刺猬）和Wnt信号通路，从而增强脂肪形成。此外，DYRK 1B促进了关键的促分化酶葡萄糖-6-磷酸酶的表达。R102 C等位基因通过增强这些效应显示出增益功能活动。第二个突变，取代脯氨酸组氨酸90，被发现与一个种族不同的家庭类似的临床综合征共分离。这些发现表明DYRK 1B在脂肪形成和葡萄糖稳态中的作用，并将其功能改变与代谢综合征的遗传形式相关联。（由美国国立卫生研究院资助。
Genetic analysis has been successful in identifying causative mutations for individual cardiovascular risk factors. Success has been more limited in mapping susceptibility genes for clusters of cardiovascular risk traits, such as those in the metabolic syndrome. We identified three large families with coinheritance of early-onset coronary artery disease, central obesity, hypertension, and diabetes. We used linkage analysis and whole-exome sequencing to identify the disease-causing gene. A founder mutation was identified in DYRK1B, substituting cysteine for arginine at position 102 in the highly conserved kinase-like domain. The mutation precisely cosegregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Functional characterization of the disease gene revealed that nonmutant protein encoded by DYRK1B inhibits the SHH (sonic hedgehog) and Wnt signaling pathways and consequently enhances adipogenesis. Furthermore, DYRK1B promoted the expression of the key gluconeogenic enzyme glucose-6-phosphatase. The R102C allele showed gain-offunction activities by potentiating these effects. A second mutation, substituting proline for histidine 90, was found to cosegregate with a similar clinical syndrome in an ethnically distinct family. These findings indicate a role for DYRK1B in adipogenesis and glucose homeostasis and associate its altered function with an inherited form of the metabolic syndrome. (Funded by the National Institutes of Health.)